Acute Fluoxetine Administration Improves Intermittent Hypoxia‐induced Inspiratory Burst Amplitude Deficits During Peak LPS‐induced Neuroinflammatory Phase in Anesthetized Spontaneously Breathing Adult Male Rats

Abstract

Studies examining the impact of neuroinflammation on various aspects of neural control of breathing typically use systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) and evaluate alterations in ventilatory control during either the induction (~2–4 hr) or resolution (~24 hr) phases of the acute neuroinflammatory response. Changes in LPS‐regulated pro‐inflammatory gene/protein expression, however, have been shown to peak at ~4–6 hrs following LPS exposure, but little is known about the impact of LPS‐induced neuroinflammation on ventilatory control at this time point. Systemic LPS administration has also been shown to increase serotonin (5‐HT) transporter activity and reduce 5‐HT levels. Since numerous inspiratory motor behaviors are 5‐HT‐dependent, including some hypoxic ventilatory behaviors, LPS‐induced changes in 5‐HT could contribute to ventilatory deficits noted in LPS‐induced neuroinflammation studies. To begin to address these issues, we examined the impact of peak phase LPS‐induced neuroinflammation on inspiratory motor behaviors elicited by intermittent hypoxia (IH) in urethane‐anesthetized vagal intact spontaneously breathing adult male Sprague‐Dawley rats in both the absence and presence of acute administration of the SSRI fluoxetine hydrochloride (FLX). Beginning at ~4 hr after systemic LPS (3 mg/kg, ip) or saline (CON) treatment, basal (BL) diaphragm EMG activity was recorded for ~30 min (40% O2), FLX (10 mg/kg) or vehicle (VEH, 0.9% saline) was injected (iv) and allowed 30 min to exert steady‐state effects, and then IH exposure composed of 5 alternating 3‐min episodes of hypoxia (11% O2; 2%CO2) and hyperoxia (40% O2) was delivered, after which the rat was allowed to recover. We found that during the first 30–60s following FLX injection in both CON‐ and LPS‐treated rats, burst amplitude (by ~12%) and frequency (by ~40%) were increased, after which amplitude returned to BL levels and frequency attained a new steady‐state ~10% above BL levels; VEH injection was ineffective in altering either burst amplitude or frequency. As expected during IH exposure in CON‐treated VEH‐injected rats, a robust increase in burst frequency and amplitude were observed with the subsequent hypoxic exposures eliciting progressive augmentation of burst amplitude (PA; IH1, ~45%; IH5, ~65%). In contrast in CON‐treated FLX‐injected rats, IH‐induced amplitude effects were markedly attenuated (IH1‐IH5, ~11–21%), and similar to those seen during IH exposure in LPS‐treated VEH‐injected rats (~7–11%). In LPS‐treated FLX‐injected rats, however, an increase in both burst amplitude and PA (IH1, ~19%; IH5, ~35%) were noted. Similar IH‐induced increases in burst frequency and post hypoxic frequency decline were also observed in both LPS‐ and CON‐treated FLX‐ and VEH‐injected rats. These preliminary observations suggest that acute FLX administration may partially correct the blunted increase in burst amplitude and induce PA in response to IH exposure during peak phase in LPS‐treated rats albeit similar FLX treatment appears to impair IH‐induced amplitude effects in CON‐treated rats.Support or Funding InformationNIH NS101737; SBU Thomas Hartman Center for Parkinson’s Disease Research